Apoptosis and the Response to Anti-Cancer Drugs

Earlier studies from Dr. Kaufmann's Anticancer Drug Action Lab provided some of the first biochemical evidence that conventional and targeted anti-cancer drugs induce programed cell death, also called apoptosis, in susceptible cells. The studies also showed that selective protein degradation occurs during this process and that intracellular cysteine proteases called caspases contribute to this degradation.

Building on these earlier results, current studies in our lab focus on understanding the pathways that lead to caspase activation and the mechanisms that regulate those pathways.

These studies have important implications for understanding why some cancers respond to chemotherapy or immunotherapy and others don't.

One pathway leading to apoptosis, the so-called extrinsic or death receptor pathway, involves tumor cell killing that is initiated by cytotoxic T lymphocytes and natural killer cells.

Our research team previously showed that death receptors, which must be present on the cell surface in order for this pathway to be activated, are inhibited from going to the cell surface when the signaling molecule protein kinase Cβ is activated. Conversely, expression of these death receptors is increased by treatment with poly-(ADP-ribose) polymerase (PARP) inhibitors.

These observations, which are currently being explored in greater detail, lay the foundation for efforts to increase the efficacy of immunotherapy by modulating the death receptor pathway in various tumors. In addition, our recent studies have implicated the death receptor pathway in the TP53-independent anti-leukemic effects of inhibitors of the kinases Chk1, ATR and Wee1 as single agents.

The other major pathway leading to apoptosis is the intrinsic pathway, called the mitochondrial pathway. This pathway is regulated by a family of proteins called BCL2 family members that monitor the intracellular environment and regulate the integrity of mitochondria.

Two of these family members, BAX and BAK, induce cell death by punching holes in the outer mitochondrial membrane, leading to the release of mitochondrial proteins to the cytoplasm, where they activate caspases.

Our studies, which have focused on BAK, have:

  • Shown that BAK undergoes concentration-dependent autoactivation in leukemia and ovarian cancer cells, providing an explanation for the rapid killing of these cells by BH3 mimetics such as venetoclax and navitoclax while simultaneously providing a means to identify cancer cells most susceptible to these agents
  • Provided evidence that other pro-apoptotic BCL2 family members can directly activate BAK, providing new insight into the mechanism of action of a variety of anti-cancer drugs, including proteasome inhibitors (bortezomib), NEDD8 activity enzyme inhibitors (pevonedistat), mTOR inhibitors (MLN0128), farnesyltransferase inhibitors (tipifarnib), and conventional anti-cancer drugs
  • Demonstrated that HIV protease can cleave the cellular protein procaspase 8 to an enzymatically inactive fragment that directly activates BAK, providing new insight into HIV-mediated T cell depletion

Our current studies are designed to better understand the process of BAK activation and the mechanism by which this critical pro-apoptotic protein permeabilizes the outer mitochondrial membrane. Combined with the other studies in the Anticancer Drug Action Lab, our studies of apoptotic pathways are providing new insight into factors that govern cancer cell sensitivity to targeted anti-cancer agents and immunotherapy, while also elucidating the mechanisms of resistance to a variety of novel anti-cancer agents.